Empirical Data Confirm Autism Symptoms Related to Aluminum and Acetaminophen Exposure

Abstract

Autism is a condition characterized by impaired cognitive and social skills, associated with compromised immune function. The incidence is alarmingly on the rise, and environmental factors are increasingly suspected to play a role. This paper investigates word frequency patterns in the U.S. CDC Vaccine Adverse Events Reporting System (VAERS) database. Our results provide strong evidence supporting a link between autism and the aluminum in vaccines. A literature review showing toxicity of aluminum in human physiology offers further support. Mentions of autism in VAERS increased steadily at the end of the last century, during a period when mercury was being phased out, while aluminum adjuvant burden was being increased. Using standard log-likelihood ratio techniques, we identify several signs and symptoms that are significantly more prevalent in vaccine reports after 2000, including cellulitis, seizure, depression, fatigue, pain and death, which are also significantly associated with aluminum-containing vaccines. We propose that children with the autism diagnosis are especially vulnerable to toxic metals such as aluminum and mercury due to insufficient serum sulfate and glutathione. A strong correlation between autism and the MMR (Measles, Mumps, Rubella) vaccine is also observed, which may be partially explained via an increased sensitivity to acetaminophen administered to control fever.

Full text

Entropy 2012, 14, 2227-2253; doi:10.3390/e14112227
entropy
ISSN 1099-4300
www.mdpi.com/journal/entropy
Review
Empirical Data Confirm Autism Symptoms Related to
Aluminum and Acetaminophen Exposure
Stephanie Seneff 1,*, Robert M. Davidson 2 and Jingjing Liu 1
1 Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology,
Cambridge, MA 02139, USA; E-Mail: jingl@csail.mit.edu (J.L.)
2 Internal Medicine Group Practice, PhyNet, Inc., Longview, TX 75604, USA;
E-Mail: patrons99@yahoo.com (R.M.D.)
* Author to whom correspondence should be addressed; E-Mail: seneff@csail.mit.edu;
Tel.: +1-617-253-0451.
Received: 24 September 2012; in revised form: 16 October 2012 / Accepted: 5 November 2012 /
Published: 7 November 2012
Abstract: Autism is a condition characterized by impaired cognitive and social skills,
associated with compromised immune function. The incidence is alarmingly on the rise,
and environmental factors are increasingly suspected to play a role. This paper investigates
word frequency patterns in the U.S. CDC Vaccine Adverse Events Reporting System
(VAERS) database. Our results provide strong evidence supporting a link between autism
and the aluminum in vaccines. A literature review showing toxicity of aluminum in human
physiology offers further support. Mentions of autism in VAERS increased steadily at the
end of the last century, during a period when mercury was being phased out, while
aluminum adjuvant burden was being increased. Using standard log-likelihood ratio
techniques, we identify several signs and symptoms that are significantly more prevalent in
vaccine reports after 2000, including cellulitis, seizure, depression, fatigue, pain and death,
which are also significantly associated with aluminum-containing vaccines. We propose
that children with the autism diagnosis are especially vulnerable to toxic metals such as
aluminum and mercury due to insufficient serum sulfate and glutathione. A strong
correlation between autism and the MMR (Measles, Mumps, Rubella) vaccine is also
observed, which may be partially explained via an increased sensitivity to acetaminophen
administered to control fever.
Keywords: autism; vaccines; MMR; HEP-B; glutathione; sulfate; cholesterol sulfate;
aluminum; mercury; acetaminophen
OPEN ACCESS

Entropy 2012, 14 2228
PACS Codes: 87.19.xm; 87.19.xt; 87.19.xw; 87.18.Vf; 87.18.Sn; 87.19.lk; 87.19.lv;
87.19.um; 87.19.uj
1. Introduction
Autism, and, more broadly, autism spectrum disorder (ASD), is a condition characterized by
impaired cognitive and social skills [1], along with a compromised immune function [2–5]. It can now
no longer be denied that the incidence of ASD is alarmingly on the rise in the U.S. [6]. While it has
been suggested that the observed increase in rates may be due mainly to a change in diagnosis criteria,
the actual criteria have changed very little from 1943 to DSM-IV-TR [7–9]. Despite considerable
research efforts devoted to trying to uncover the cause(s) of autism, thus far no definitive answer
seems available from the research literature. However, the fact that ASD rates have been rapidly
increasing over the last two decades strongly points to an environmental component. Indeed, autism is
recently being reframed from being a strictly genetic disease to representing a complex interaction
between genetics and environmental factors, suggesting that we should focus our attention more on
“environmentally responsive genes” [10].
The ASD community has maintained a long-standing conviction that vaccination plays a causative
role in ASD [11], an idea that has been vehemently denied by the vaccine industry [12], but
nonetheless is still hotly debated [13]. A study published in 2011 has confirmed a positive correlation
between the proportion of children who received vaccinations in each state over the interval from 2001
to 2007 and the incidence of autism or speech and language impairment [14]. For each 1% increase in
vaccination rate, 680 additional children were diagnosed with autism or speech delay.
In [15], we proposed that a causative factor in autism is an inadequate supply of cholesterol sulfate,
both in utero and postnatally. Cholesterol sulfate synthesis in the skin is catalyzed by sun exposure [16].
We hypothesized that autism may be induced by a combination of inadequate dietary sulfur and
insufficient sun exposure to the skin, for both the mother and the child. A meta-study involving
oxidative-stress related biomarkers present in association with autism identified a consistent deficiency
in reduced glutathione [17], an important sulfur-based antioxidant that also plays a role in detoxifying
aluminum. We proposed that cysteine, the rate-limiting amino acid involved in the synthesis of
glutathione [18], is depleted through redirection into an alternative pathway to produce sulfate, due to
the impaired sulfate synthesis from thiosulfate in the skin.
A recent study of biomarkers for 28 individuals with an ASD diagnosis showed reduced
glutathione, cysteine, and sulfate compared to controls, and the authors proposed that a reduced
detoxification capacity might impede mercury excretion [19]. These same authors observed a marked
reduction in serum sulfate in association with ASD in another paper [20]. In particular, the level of free
sulfate in the blood stream was only 33% of the level found in control subjects. We hypothesize that
sulfate deficiency results in insufficient ionic buffering in the vasculature, with grossly inadequate
sulfation of the extracellular matrix proteins that are essential for proper colloidal suspension of
particles and cells [21,22].

Entropy 2012, 14 2229
Glutathione [23] and sulfate [24] are also essential for the detoxification of xenobiotics and
commonly administered drugs like acetaminophen in the liver. Selenium, a trace metal in the same
column of the periodic table as oxygen and sulfur, has been shown to protect against acetaminophen
toxicity [25], and it has also been shown to be severely depleted in hair and nail samples from
individuals on the autism spectrum [26].
A possible link has been found between acetaminophen and both autism and asthma [27]. The
association of both asthma [28] and eczema [29] with ASD can be explained as an inadequate supply
of filaggrin, due to the fact that cholesterol sulfate in the epidermis stimulates the production of
profilaggrin, its precursor [30]. Filaggrin plays an essential role in maintaining the epithelial barrier [31],
and its impairment leads to increased risk of both asthma [32] and eczema [33,34]. Thus cholesterol
sulfate deficiency provides an explanation for the multiple links among autism, acetaminophen,
asthma, and eczema.
It has been demonstrated that chronic aluminum exposure in rats induces depletion of glutathione in
the liver as well as a significant reduction in the synthesis of bile acids [35], which are conjugated with
taurine, the only sulfonic amino acid [36]. Taurine administration in conjunction with aluminum
greatly ameliorates the adverse effects of aluminum on the liver, and this was explained as possibly
due to the ability of the sulfonate group in taurine to bind with heavy metals such as aluminum [37].
These results suggest that glutathione and taurine are both involved in aluminum detoxification in the liver.
Many children with autism have a low amount of serum glutathione, with a larger fraction of it
oxidized to GSSG [38]. Furthermore, increased use of antibiotics leads to an alteration in gut flora
which impairs the ability to detoxify toxic metals like mercury. Dimercaptosuccinic acid (DMSA), an
organosulfur compound with two thiol groups, has been found to be effective in ameliorating the
symptoms of autism in placebo controlled studies [39], likely through its ability to enable the excretion
of toxic metals such as lead and mercury [40]. It also led to a normalization of glutathione levels in red
blood cells [40].
Vitamin D deficiency has been hypothesized to be a risk factor for autism [41]. The over-zealous
application of sunscreen is strongly implicated in autism, not only because sunscreen interferes with
the production of vitamin D3 and cholesterol sulfate but also because it often contains aluminum,
particularly the high Sun Protection Factor (SPF) sunblock products. Aluminum, due in part to its +3
ionic charge, is highly toxic to biological systems [42,43] as will be described more fully in Section 2.1.
Indeed, there are no known life forms that utilize aluminum in any biological systems. The poorly
developed barrier function of the autistic child’s epidermis would likely lead to an increased
penetration of aluminum through the skin. Furthermore, their serum sulfate deficiency leads to an
impaired ability to dispose of aluminum. Aluminum would therefore be expected to accumulate over
time, and, due to increased permeability of the blood brain barrier associated with autism [44], would
almost certainly interfere with neuron function.
In the next section, we examine the evidence from the literature that aluminum toxicity may play a
role in vaccine adverse reactions, and we describe available theories for the mode of toxicity of
aluminum and other toxic metals.

Entropy 2012, 14 2230
2. Aluminum and Mercury in Vaccines
It has recently been proposed that aluminum, commonly used in vaccines as an adjuvant, may be
the most significant factor in adverse reactions, and, furthermore, that the nervous system is especially
vulnerable to aluminum toxicity [45]. Vaccine clinical trials often include aluminum in the placebo, at
the same or greater concentrations than the amount found in the vaccine [46–49]. A comparable
number of adverse reactions between vaccine and placebo in these trials suggests that aluminum is an
important source of toxicity in the vaccine. Indeed, intraperitoneal injection of aluminum-adsorbed
vaccine in mice caused a transient rise in aluminum in brain tissues [50].
The Food and Drug Administration (FDA) has set an upper limit of 5 micrograms Al/kg/day for
neonates and individuals with impaired kidney function [51]. A highly informative recent review of a
possible relationship between aluminum toxicity and Alzheimer's disease [52] also discussed issues
related to the aluminum burden in children's vaccines. There, it was pointed out that children today
receive a cumulative aluminum burden from vaccines that may exceed the FDA limit by a factor of 50.
The vaccine industry has a difficult task in designing vaccines that are both safe and effective [53].
The use of weakened but live pathogens can lead to vaccine-induced disease in children with an
impaired immune system, yet debris from dead pathogens may not always cause a sufficient reaction
to induce the production of antigen-specific memory CD8 T-cells, required for protection against
future exposure. The industry widely reports success in creating vaccines with dead pathogens by
adding adjuvants such as aluminum, lipopolysaccharide (LPS) from E. coli, and polycationic
surfactants, to further stimulate the immune response [54]. It remains unclear exactly how aluminum
achieves its effect of enhancing the immune reaction, but aluminum adjuvants are now thought to
impact on humoral systems via their positive influence on the inflammasome complexes [55].
Another industry-claimed basis for adding aluminum or mercury to vaccines is to increase the
stability of the antigen in long-term storage. It has been shown that the rate of acid-catalyzed
hydrolysis of glucose-1-phosphate is significantly slower when the molecule is adsorbed to aluminum
hydroxide adjuvant, increasing the effective pH of the environment by 2 pH units [56]. This effect
would however also interfere with the human body’s ability to break down the antigen from the
vaccine, which may partially explain the heightened immune reaction.
Based on concerns that the mercury (49.6% by weight) in thimerosal might be contributing to
autism [57], the industry made an effort to significantly reduce the amount of mercury present in
vaccines beginning in the late 1990’s [58]. In parallel, they began storing the vaccines in
individualized glass vials—to avoid the ostensible need for a preservative to reduce the danger of
contaminating repeated invasions of multidose vials. However, this raises another concern, as
aluminum can be leached out of the glass vial and the rubber stopper during storage [59]. This same
issue can also affect premature infants given serum albumin infusions, resulting in an inadvertent
exposure to aluminum very early in life [60].
Glass contains aluminum oxide at levels ranging from 1.9% to 5.8% [61]. Leaching from a
container is an ongoing process until the product is used. Storage containers contribute significantly to
aluminum contamination in human serum albumin products. Because of impaired renal function,
dialysis patients are at risk to developing encephalopathy and a severe form of dementia due to their
inability to dispose of the small amounts of aluminum that could be present in the dialysis water base [62],

Entropy 2012, 14 2231
although this problem has been largely corrected today. We suggest that the effect of aluminum on the
brain of a person already on the autism spectrum may manifest a similar pathology.
Mechanisms of Aluminum and Mercury Toxicity
Aluminum is one of the most common elements on Earth, yet no biological system has yet found a
use for it. Aluminum is expected to induce biosemiotic entropy through multiple pathways [22,63,64].
Its +3 charge and highly kosmotropic properties make it extremely destructive in water-based
biological systems. One purely biophysical mechanism might involve its direct effect upon interfacial
water tension. Another less direct mechanism might involve competition for calmodulin binding and
the initiation of a signaling cascade with profound consequences. Both phenomena would likely induce
biosemiotic entropy through both supramolecular and epigenetic effects. Thus, a focus limited solely to
genetics and molecular biology is likely to be misguided. Long-range, dynamically-structured
interfacial water is the medium which, when energy-loaded, both conveys the biological message and
overcomes the thermal diffusion problem [65,66]. When interfacial water is energy-unloaded, the
biological message is corrupted: unfolded protein responses and apoptosis follow. We posit that
aluminum is a sine qua non of biosemiotic entropy―an exogenous interfacial water stressor.
Since aluminum is a known neurotoxin, there is no safe level. The central nervous system is
particularly susceptible to the deleterious effects of aluminum. Exposure of human neuronal cells to a
low concentration (100 nM) of aluminum sulfate induces a response that emulates the gene expression
changes associated with Alzheimer's disease [67]. Recently, a group of researchers investigated the
effect of aluminum sulfate on an in vitro culture of human neural cells [63], which was directly
compared to the effect of magnesium-, iron- and zinc sulfate. They confirmed that, by contrast with the
other salts, aluminum sulfate had an unusual and significant ability to induce NF-κB signaling and
subsequent reactive oxygen species (ROS), mediated by down-regulation of the important
inflammation inhibitor, complement factor H (CFH). In a subsequent paper, the sulfates of 13 different
cations were assessed for their ability to induce ROS in neuronal cultures, and aluminum was
determined to stand out among all the ions studied for its remarkable ability to induce ROS, even
compared with mercury and lead [64]. Aluminum induced a response that was a factor of seven higher
than that of mercury and a factor of three higher than that of lead.
Aluminum adjuvants damage and rupture the phagolysosomes, generate reactive oxygen species,
and induce potassium efflux from the cell [68]. Our research has led us to suspect disruption of
calmodulin (CaM) signaling as one of the most destructive aspects of aluminum toxicity. CaM
functions as a calcium sensor and signal transducer that regulates a number of distinct protein targets,
influencing many different cellular functions [69]. Upon binding to calcium, CaM undergoes a
conformational change, and subsequent transformations such as phosphorylation, acetylation, and
methylation can modulate its action.
The aluminum ion is a potent inhibitor of voltage-gated calcium channels in the brain [70].
Normally, calmodulin (CaM), after binding to calcium, stimulates nitric oxide (NO) production by
both endothelial nitric oxide synthase (eNOS) and neuronal nitric oxide synthase (nNOS). An
investigation of the interaction of aluminum ions with bovine brain CaM [71], confirmed that
aluminum binds to CaM with an affinity that is an order of magnitude stronger than that of calcium.

Entropy 2012, 14 2232
Interaction with aluminum induces a conformational change in the molecular structure. A molar ratio
of 4:1 for aluminum/CaM completely blocks the activity of CaM-dependent phosphodiesterases. Highly
hydrated aluminum ions profoundly influence the protein’s flexibility and disrupt its structural integrity.
Severe impairment of astrocyte function has been demonstrated in conjunction with aluminum
exposure [72,73]. Aluminum appears to interfere with iron-sulfur clusters in the mitochondria, causing
impaired ATP synthesis, excess production of reactive oxygen species, and impaired formation of the
cytoskeleton, which is essential for the cell’s function in maintaining the health of neighboring
neurons. Cells exposed to as little as 0.01 mM concentrations of aluminum show a disrupted actin
cytoskeleton and a drastic morphological change into a globular configuration. Due to its cationic +3
charge, aluminum directly causes in vitro aggregation of neurofilaments characteristic of many human
neurological diseases [42].
NO Synthesis by eNOS after aluminum exposure: An excessive production of NO can result in
anaphylactic shock, a life-threatening allergic reaction, associated with overexuberant vasodilation and
a precipitous drop in blood pressure. A recent experiment with mice triggered anaphylactic shock by
exposing the mice to an injection containing aluminum hydroxide and pertussis toxin [74]. This
resulted in the excess synthesis of NO by eNOS, and a subsequent signaling cascade, mediated by the
phosphatidyl inositol-3 kinase (PI3K) pathway. We hypothesize that aluminum’s propensity to bind
strongly to CaM mediated this response.
Aluminum’s Effects on Neurons: A novel characteristic of the autistic brain is that it is larger than the
non-autistic brain at the age of two or three [75], an effect that is hypothesized to be due to an impaired
glutamate-mediated neuronal-pruning developmental phase. Overgrowth is observed in cerebral,
cerebellar, and limbic structures underlying cognitive, social, emotional, and language functions [76].
Significantly, a study involving prenatal aluminum exposure revealed an effect on neurons in rat brains
suggesting resistance to apoptosis following glutamate signaling, a potentially related phenomenon
[77]. Glutamate-induced neuronal death was significantly reduced in primary cultures of cerebellar
neurons taken from aluminum-exposed rats. The effect was shown to be mediated by a disruption of
CaM signaling to induce nNOS activity, analogous to the CaM-related effect of aluminum in
endothelial cells.
Aluminum and Mercury Impact Zeta Potential and Sulfate Recycling: Zeta potential (ZP) is defined by
the rate at which a charged particle suspended in a medium will travel in an applied electric field. A
high negative value for zeta potential is essential for maintaining blood as a colloidal suspension [21]:
cells and complex molecules suspended in the blood avoid flocculation through a negative charge field
maintained in the immediate surrounding space. One of the main functions of serum albumin is to
control colloid stability in the blood [78].
Both mercury and aluminum bind strongly to cysteines in serum albumin in the blood stream [79,80].
The adsorption of aluminum onto serum albumin has a profound effect on serum zeta potential (ZP) [80],
driving it even to positive values at physiological pH with sufficient concentrations of aluminum
hydroxide. It is believed that much of the mercury that is filtered into the proximal tubular lumen in the
glomerulus of the kidney is present primarily as a conjugate of albumin, bound to the sulfhydryl group
of a cysteine constituent [79]. Thus, positively-charged mercuric Hg2+ salts bound to serum albumin
would be expected to cause a similar effect as aluminum on serum ZP.

Entropy 2012, 14 2233
Mercury has a great predilection for bonding to reduced sulfur atoms, especially those in thiol-
containing molecules such as glutathione, cysteine, homocysteine, and albumin. The affinity of
mercury towards oxygen-or nitrogen-containing ligands is about 10 orders of magnitude lower [79]. A
study on oral exposure to methylmercury in mice confirmed that the methylmercury is absorbed, taken
up by the liver, and then exported via the bile acids, likely bound to bio-organic sulfate. These
researchers demonstrated a complete inability to dispose of methylmercury in neonate animals,
confirming that newborns are much more susceptible to mercury toxicity than adults [81]. It was
shown that this impaired disposal was due in part to insufficient glutathione in the liver.
A study on infant monkeys confirmed that the ethylmercury in thimerosal that is injected into the
primate is more readily stored as inorganic mercury in the brain than is orally-delivered ethylmercury,
and that inorganic mercury tends to linger longer in the tissues [82]. Exposure to thimerosal leads to
abnormal glutamate transport in neurons in mouse hippocampi [83]. Mercury also has an adverse
effect on sulfate recycling in the glomeruli, leading to a net loss of sulfate via the urine. A noticeable
reduction in the production of dermatan sulfate is associated with mercury exposure, via an effect on
the mesangial cells [84]. Thus, mercury would be expected to either build up to toxic levels or further
reduce sulfate bioavailability in the child with autism.
3. Related Work
3.1. MMR Vaccine
It has been suggested that the measles, mumps, and rubella (MMR) vaccine may be contributing to
the increased prevalence of autism in recent decades [85]. A large population-based study involving
children born in Denmark between 1991 and 1998 has seemingly proven otherwise [12]. In comparing
440,000 vaccinated children with 96,000 unvaccinated children, the authors claimed that no significant
difference in the incidence of autism was detected between the two groups. However, there are several
concerns with this study. The first one is that the reasons for not vaccinating were not determined, and
it is likely that important reasons might have been the presence of autism in a close family member,
thus predisposing the non-vaccinated population to autism due to the inheritability of the disease (or,
the fact that the mother still has the nutritional deficiency that caused the older sibling’s autism).
Another possibility for exclusion is an actual diagnosis of autism, or an adverse reaction to some other
vaccine, a feature that is also likely associated with increased risk of autism.
The second concern has to do with the way the data were analyzed. It would seem to be logical to
divide the 0–3 age group into two subsets, one before 15 months and one after 15 months, in order to
more easily assess the relevance of MMR (administered at 15 months) to the autism diagnosis. But the
authors chose to combine all cases under 3 into a single category in the summary table they presented
in the paper. Furthermore, any diagnoses before 15 months were inexplicably put into the “not-
vaccinated” group, whereas they should have simply been excluded. The non-vaccinated group had,
relatively speaking, more diagnoses before three years, but some unknown percentage of these,
possibly even all of them, occurred before the 15-month cut-off.
By contrast, substantially fewer cases of autism were diagnosed in the window between 3 and 5
years in the not-vaccinated group, if the two populations are distributed equally by age. From the

Entropy 2012, 14 2234
numbers in their table, one can compute a 41% increased relative frequency of autism diagnosis in the
vaccinated versus the unvaccinated population in this age range, a number that might well have been
statistically significant had it been singled out.
Finally, it is likely that other vaccines in addition to MMR play a role in autism, particularly since,
unlike many vaccines, MMR contains neither thimerosal nor aluminum. MMR is often administered
simultaneously with DTaP, an aluminum-containing vaccine. The synergistic and cumulative effects of
multiple vaccines would likely lead to nonlinear enhancement of adverse events.
It has been claimed that Denmark had excluded thimerosal from all vaccines prior to the birth of
any of the children in the study [86]. If this is true, then this is in stark contrast to the U.S. policy,
where thimerosal still appears in several vaccinations given to young children, including Hep-B and
HiB Titer. Aluminum is present in several of the vaccines, for example, Hep-B, PREVNAR, all of the
DTaP formulations, and H1N1 flu vaccine multidose vials.
3.2. Other Related Work
Aluminum adjuvants are the only adjuvants approved for use. They are known to enhance the
specificity, intensity, and duration of the immune response, leading to improved long-term protection
from the disease [87]. A workshop was held in 2002 in San Juan, Puerto Rico, addressing the issues
associated with aluminum in vaccines, with a particular focus on myalgias and fatigue in adults
following vaccination exposure to aluminum [88]. A recently published article seriously addresses the
question of the safety of aluminum adjuvants in vaccines, pointing out the neurotoxicity of aluminum [45].
A U.S.-based study published in 2010 [89] determined that a three-fold increased risk to autism was
associated with neonatal administration of Hepatitis B (Hep-B) vaccine prior to 1999, compared with
either no vaccination or a delay until after the first month of age. Notably, Hep-B contains both
aluminum and mercury.
Several researchers have reported increased frequencies of either sudden death or other health crises
such as anaphylaxis or cardiorespiratory problems in association with vaccines. In [90], it was reported
that six infants died suddenly within 48 hours of having received a hexavalent vaccine, a frequency
that is abnormally high compared to the risk of SIDS in the general population. Unexpectedly high
SIDS rates following vaccination are also reported in [91]. Researchers in Italy [92] report that the first
vaccination carries an increased risk to SIDS in infants. In [93], through statistical analysis based on
300 cases of unexplained sudden death, a 16-fold increased risk was determined following the fourth
dose in a series of vaccinations. In [94], it was reported that the observed rate of anaphylaxis following
administration of the HPV vaccine to females aged 12 to 26 was significantly higher than the rate
observed following other vaccines. In [95], precautionary monitoring is recommended following
vaccination of premature infants, due to observed adverse reactions related to cardiorespiratory events,
as well as a substantial increase in serum levels of C reactive protein, an inflammatory marker. This
was particularly true for DTaP, an aluminum- containing vaccine, especially when it was combined
with concomitant vaccines.
Goldman and Miller [96] have previously examined the VAERS database, specifically looking at
hospitalization rates and mortality statistics as a function of the number of vaccines simultaneously
administered and of age. Linear regression analysis revealed several statistically significant trends,

Entropy 2012, 14 2235
including a positive correlation between hospitalization rates and number of vaccine doses. In addition,
mortality rates for infants under six months were significantly higher than rates for children between
six months and one year of age, suggesting increased sensitivity of neonates. The authors suggested
delaying administering of vaccines as a strategy for reducing risk of a severe adverse reaction. These
authors also emphasize the value of VAERS as an important postmarketing safety surveillance tool.
Studies on adverse reactions for vaccination of adults have also been performed. A 2002 study of
the VAERS database related to Hepatitis B vaccine confirmed a significant number of adverse
reactions in adults [97]. A case study published in 2009 described an adult’s profound adverse reaction
to multiple vaccinations containing aluminum, resulting in aluminum hydroxide deposits accumulating
in macrophages in muscle cells, along with debilitating muscle pain and weakness associated with
chronic fatigue syndrome and macrophagic myofasciitis [98].
4. Our Studies with U.S. CDC VAERS Database
The Vaccine Adverse Event Reporting System (VAERS) is a surveillance system implemented by
the U.S. government, which allows doctors and/or patients to report any adverse reactions observed in
association with vaccines. The cover page emphasizes that the data report only an association rather
than a confirmed causal relationship. Data are readily available for download from the web site,
“http://vaers.hhs.gov/index” beginning in the year 1990. In this section, we will present the results of
several experiments we conducted with the VAERS database, using standard statistical techniques
based on word frequency information.
In order to validate our methods, we first examined the differences between a set of records
associated with autism and a comparison set drawn randomly from the remaining records. The autism-
related data set contained all cases where the word “autism” or the word “autistic” showed up
somewhere in the report. This yielded a total of 1,734 entries. The comparison set was constructed by
randomly sampling from the remaining entries (~340,000 reports), but in such a way that the age
distribution was exactly matched to the distribution obtained from the records associated with autism,
obtaining a record of identical size (1,734) to that of the autism set. We performed a statistical analysis
of selected words and phrases in the “symptom text” field as well as in the five “symptoms” fields in
the associated VAERSSYMPTOM files.
We used an established method based on log likelihood ratio, as described in [99,100], which
provides a p-value associated with the likelihood that the observed distribution bias of the word or
phrase could have occurred by chance. To improve statistical power, we collected the most frequently
occurring words in the “symptoms” fields, and organized them into reasonable classes. For example,
“abdominal pain,” “abdominal discomfort,” “abdominal distention,” and “abdominal tenderness”
collectively represented the class “abdominal pain.”
Table 1 shows all of the words or phrases that were biased towards the autism data set with a
p-value at or below 0.05. Constipation [101], anxiety [102], asthma [28], eczema [29] and premature
birth [103] have all been found to be associated with autism in the research literature. We consider it to
be a validation of our methods that we detected these features with a statistically significant p-value.
This also implies that the VAERS database may be useful for predicting associations between
symptoms and conditions, irrespective of any claim about the effects of a particular vaccine.

Entropy 2012, 14 2236
Prematurity would be expected to be a risk factor for ASD, as the cholesterol sulfate supply from the
placenta is normally greatly increased toward the end of pregnancy [104]. Premature infants may also
suffer from additional aluminum exposure through albumin infusions [60].
Table 1. Skewed distributions of symptom words between two data sets: a set of vaccine
adverse reactions associated with autism, and an age-matched set of other vaccine
reactions. C1: number of entries in autism set containing this symptom; C2: Number of
entries containing this symptom in the comparison set. p-value: the likelihood that the
distribution would have occurred by chance according to a log-likelihood ratio formulation.
Symptom C1 C2 p-value
Anxiety 49 2 0.011
Constipation 41 0 0.012
Infection 54 6 0.013
Ear infection 32 3 0.029
Eczema 18 0 0.044
Premature 20 1 0.046
Asthma 24 3 0.048
Pneumonia 19 1 0.050
Note: In this and subsequent tables, we use the word “symptom” inclusively to refer to signs,
symptoms and conditions.
Three associated words suggestive of a weakened immune system, “infection,” “ear infection,” and
“pneumonia” support the observation from the literature that autism is associated with immune
dysfunction [2]. It has also been demonstrated that children with the autism diagnosis exhibit a
heightened immune response to antigen stimulation [105], which we propose is caused by their global
deficiency in sulfate supply. Thus, their increased vulnerability to infection in general likely parallels
an increased likelihood of an adverse reaction to vaccines, particularly vaccines like MMR where the
pathogen is only weakened but not killed.
4.1. Distribution of Vaccine Types in Autism versus Controls
Another aspect we investigated from the VAERS database is to compare the distribution of type of
vaccine administered between the autism-related events and the non-autism-related events. The results
are shown in Table 2. We looked only at data for children under 6 years old, and we computed the
percentage of events associated with each vaccine type in each data set. As shown in Table 2, MMR
was significantly more likely to be associated with autism (41% of the autism-associated events as
against only 15% of the non-autism associated events, with a ratio of 2.67). HiB Titer and hepatitis
were also over-represented in the autism group, although to a lesser degree.
Since MMR contains neither aluminum nor mercury, it is puzzling that children with the autism
diagnosis seem to be highly sensitive to it. We have not examined the records in detail to determine
what percentage had autism before receiving the vaccine, and, in fact, in many cases this information is
not available from the VAERS record, which may simply list autism as a feature. An interesting theory
relating the MMR vaccine to ASD involves a proposed toxic reaction to the acetaminophen
(paracetamol) administered to control fever following vaccination [25,106]. It has been proposed that

Entropy 2012, 14 2237
acetaminophen may mediate oxidative stress and neurotoxicity in autism [107], and acetaminophen has
been demonstrated to be toxic to developing mouse cortical neurons in vitro [108].
Table 2. Percentages of events associated with different vaccine types in the autism data set
versus the not autism data set, and the ratio between the two. The numbers add up to more
than 100% due to the fact that multiple vaccines are often simultaneously administered.
Pathogen Percent Autism Percent Not Autism Ratio
MMR 40.94 15.35 2.67
Hep-B 16.02 8.71 1.84
HiB Titer 15.02 8.40 1.80
DTaP 42.53 43.93 0.97
Polio 15.60 16.34 0.96
Varicella 15.77 16.68 0.95
Pneumonia 8.81 10.29 0.86
Rotavirus 0.25 3.29 0.076
Total 154.94 122.99 1.26
A study of the ability of children with the autism diagnosis to dispose of paracetamol found that the
ratio of paracetamol-sulfate to paracetamol-glucuronide (PS/PG) in the urine of children with severe
autism following acetaminophen administration was significantly lower (p < 0.00002) than that
measured for normal controls [109]. This result strongly suggests an impaired ability to metabolize
toxic substances via a sulfation pathway. If the MMR vaccine is administered simultaneously with
DTaP, an aluminum-containing vaccine (as is often the case), then the acetaminophen would likely
interfere with the child’s ability to dispose of the aluminum.
The autism-associated events exhibited an 84% increased frequency of reactions to hepatitis, and an
80% increased frequency of reactions to HiB Titer. While we included both Hep-A and B in the
search, the matches were almost exclusively to Hep-B. Hep-B contains aluminum hydroxide and
thimerosal, and HiB Titer contains thimerosal.
Hep-B is administered usually within 24 hours of birth, and most definitely in the first two months
of life, and HiB Titer is administered three or four times before the age of 15 months. These two
vaccinations would thus cause an accumulation of mercury and aluminum along with a depletion of the
bioavailability of sulfate prior to the MMR vaccine in the vulnerable child, leaving them more
susceptible to an infection arising from the live virus administered in MMR, and a subsequent dose of
Tylenol (acetaminophen) to curb fever.
Another aspect we investigated was the number of events associated with autism as a function of
the year the event was reported. Realizing that the report date and the event date can sometimes be
separated by several years, we reported this detailed profile over time based on the event date instead
of the report date. In cases where the event date was unavailable, we used the report date instead. The
results are shown in Figure 1. It is striking that the number rises steadily over the last five years of the
twentieth century, peaking around 2003. In the U.S., aluminum was allegedly phased in at the same
time that mercury was phased out [110]. If the current CDC immunization schedule [111] is followed,
babies are injected with nearly 5 mg of aluminum by 18 months of age.

E
a
w
b
a
a
b
m
4
(
r
n
t
h
c
c
“
a
a
s
s
E
ntropy 20
1
Fi
g
ur
e
menti
o
which
availa
b
Given th
a
a
nd given t
h
w
e develop
e
b
een the re
a
a
round 199
9
a
dded to th
b
urden by
2
m
ercury bu
r
4
.2.
R
elatio
n
In this n
e
i.e., for all
r
eported aft
e
n
umber of s
y
We then
h
at include
d
c
ontaining
v
c
ontained
a
“
ANTHRA
X
a
s the strin
g
For all
o
a
luminum
s
s
uggesting
t
s
ymptoms,
w
1
2, 14
e
1. Numb
e
o
ned in at
l
the event
b
le, we use
d
a
t autism i
n
h
e knowled
g
e
d the hyp
o
a
son for th
e
9
[110]. H
o
e vaccine
s
2
0%. This
r
den.
n
ship betw
e
e
xt set of
e
age grou
p
e
r 1999.
W
y
mptoms t
h
collected t
w
d
at least
o
v
accines.
S
a
ny of the
X
”. For the
g
s “HIB” or
o
f the symp
s
ubsets, all
t
hat alumi
n
w
hich are f
a
e
r of advers
l
east one o
f
occurred,
f
d
the year
o
n
cidence in
t
g
e that the
o
thesis tha
t
e
observed
c
o
wever, fo
u
s
chedule
w
could have
e
en Alumin
u
e
xperiment
s
p
s), and we
W
e perform
e
h
at were fa
r
w
o subsets
o
o
ne alumin
u
S
pecificall
y
following
“w/o alu
m
“RABIES
”
toms in th
e
of the ske
w
n
u
m
-contai
n
a
r more pre
v
0
20
40
60
80
100
120
140
160
1990 1
9
e events in
f
the fields
f
rom 1990
o
f the repor
t
t
he VAER
S
total thime
r
t
an enhan
c
c
ontinued
h
u
r doses of
a
w
ithin the n
e
masked a
n
u
m in Vacci
s
we first c
o
collected
a
e
d our wor
d
r
more prev
a
o
f incident
s
u
m-containi
n
y
, “w/ alu
m
substrings
m
inum” clas
s
”
as for this
e
table, an
d
w
ed distri
b
n
ing vaccin
e
v
alent in th
9
92 1994 199
6
VAERS w
h
in the rec
o
to 2010. F
t
instead.
S
database
c
r
osal burde
n
c
ement of
a
h
igh rates o
f
a
new alu
m
e
xt few ye
n
y drops i
n
nes and Sy
m
o
llected all
a
n age-ma
t
d
frequenc
y
a
lent after
1
s
that were
r
n
g vaccine
,
m
inum” w
a
: “DTAP”
,
s
, we elimi
n
second ex
p
d
for both
t
b
utions on
c
e
s contribu
t
e aluminu
m
6
1998 2000
2
h
e
r
e the w
o
o
rd, plotte
d
or cases
w
c
ontinued t
o
n
had been
a
luminum a
f
autism.
M
m
inum-cont
a
ars [110,1
1
n
autism ra
t
m
ptoms
of the ad
v
ched subs
e
y
counts on
1
999, as ill
u
r
eported an
y
,
and the o
t
a
s defined
,
“DTP”,
“
n
ated any t
h
p
eriment is
a
t
he before/
a
c
ounts we
r
t
e to the i
n
m
-containin
g
2
002 2004 2
0
o
rd “autism
”
d
as a func
t
w
here the e
v
o
rise after
a
significant
l
djuvant in
M
ercury wa
s
a
ining pne
u
1
1], increa
s
t
es conseq
u
v
erse event
s
e
t of all of
these data
,
u
strated in
T
y
time bet
w
t
her includi
as includi
n
“
HEP”, “P
R
h
at contain
e
a
lso shown
a
fter 1999
s
r
e highly s
i
n
creases in
g
vaccines,
0
06 2008 201
0
”
or “autist
i
t
ion of the
y
v
ent year
w
a
small dip
a
ly reduced
the vaccin
e
s
phased o
u
u
mococcal
v
s
ing the tot
u
ential to t
h
s
reported
p
the incide
n
,
and disco
v
T
able 3.
w
een 1990 a
n
ng only no
n
n
g a “vax
R
EVNAR
”
e
d these st
r
in Table 3.
s
ubsets an
d
i
gnificant,
t
these sym
p
include se
v
0
22
3
i
c” was
y
ear in
w
as not
a
round 200
0
by that tim
e
might ha
v
t of vaccin
e
v
accine we
r
al aluminu
m
h
e dec
r
eas
e
p
rior to 20
0
n
ts that we
r
v
ered a lar
g
n
d 2010, o
n
n
-aluminu
m
name” th
”
, “HPV”
o
r
ings, as w
e
d
the w/, w
/
t
hus strong
l
p
toms. The
s
v
ere reactio
n
3
8
0
,
e,
v
e
e
s
r
e
m
e
d
0
0
r
e
g
e
n
e
m
-
at
o
r
e
ll
/
o
l
y
s
e
n
s

Entropy 2012, 14 2239
such as seizure, cellulitis, cyanosis, depression, and even death. The alarming increase in seizures after
2000 is particularly disturbing in light of the known association between seizures and autism [44].
Table 3. Results of studies on adverse reactions over time, and as a function of aluminum
contents of vaccines. The table shows selected reactions which were reported far more
frequently in the “after-2000” subset than in the “before-2000” subset, with counts and p-
values for both before/after 2000 and aluminum/non-aluminum containing vaccines. See
text for details.
Symptom
C1
Before
2000
C2 After
2000 p-value C1
w/ Al+3
C2 w/o
Al+3 p-value
Seizure 636 3468 0.0000 2350 1023.2 0.00028
Injection Site Reaction 1961 4605 1.0E-8 3851 2584 0.000061
Infection 195 1552 1.0E-8 1358 927 0.0026
Swelling 8621 13218 1.0E-8 11406 8470 0.0000026
Pain 8153 12122 6.0E-8 8576 7099 0.00044
Cellulitis 760 1977 0.000001 2087 1089 0.000024
Depression 57 322 0.00023 334 143 0.0031
Death 210 558 0.0040 483 303 0.011
Fatigue 1222 1839 0.00080 1744 968 0.00011
Insomnia 81 195 0.0089 230 71 0.0025
In order to better characterize the set of symptoms that are associated with aluminum-containing
vaccines, we computed a tally of the total number of mentions of every symptom whose word
frequency was associated with aluminum-containing vaccines with a p-value less than 0.01. There
were twelve such symptom classes, namely: fatigue, seizure, blister, cellulitis, pain, swelling, injection
site macule, insomnia, injection site reaction, infection, depression, and uveitis. We compiled this
statistic based on all aluminum-containing events in the database.
We then plotted a histogram over time of the result, to be compared with the plot of the histogram
of autism mentions in the events. Results are shown in Figure 2. This plot shows a steady rise from
about 1997 to 2003. It is conceivable that the workshop on aluminum held in 2002 [88] had some
impact in reducing the aluminum burden in vaccines, although it is difficult to determine the
adjustments of aluminum adjuvantion in vaccines over time, due to lack of transparency.
Figure 3 shows the ratio of the total number of aluminum-related adverse reactions associated with
a particular year to the total number of aluminum-containing events occurring during that year. This
number rises steadily over the turn of the century, reaching above 1.0 starting in the year 2000, and
peaking at 1.4 in 2003. This means that multiple adverse reactions―cellulitis and reaction site macule,
for example, are occurring in association with a single adverse event. The peak at 2003 corresponds
well with the peak in autism-related reports. Thus there are introduced both an increase in the number
of events around 2000 as well as an increase in the potency of each event to induce a reaction. This
could be explained as an increased sensitivity to aluminum in the population, possibly due to a
synergistic effect of cumulative exposure to multiple toxins [113].

E
E
ntropy 20
1
Fi
g
ur
e
contai
n
with
a
year,
b
liste
r
infect
i
Fi
g
ur
e
contai
n
with
a
year,
f
associ
fatigu
e
site re
a
1
2, 14
e
2. Total
c
n
ing vacci
n
a
luminu
m
-c
from 1990
r
, cellulitis,
i
on, depres
s
e
3. Total
c
n
ing vacci
n
a
luminu
m
-c
f
rom 1990
ated advers
e
, seizure,
b
a
ction, infe
c
0
0
0
0
1
1
1
c
ount of s
y
n
es in VAE
R
ontaining
v
to 2010.
pain, swe
l
s
ion, and u
v
c
ount of s
y
n
es in VAE
R
ontaining
v
to 2010, a
n
e events oc
b
lister, cell
u
c
tion, depr
e
0
2000
4000
6000
8000
10000
12000
199
0
.2
.4
.6
.8
1
.2
.4
.6
1990
1991
1992
y
mptoms i
n
R
S whose
w
v
accines wi
t
Symptoms
l
ling, injec
t
v
eitis.
y
mptoms i
n
R
S whose
w
v
accines wi
t
n
d normali
z
curring in t
h
u
litis, pain,
e
ssion, and
u
0 1992 1994
1
1993
1994
1995
1996
199
n
all the ad
v
w
ord frequ
e
t
h a p-valu
e
that met t
t
ion site m
a
n
all the ad
v
w
ord frequ
e
t
h a p-valu
e
z
ed with re
s
h
at year. S
y
swelling, i
n
u
veitis.
1
996 1998 20
0
199
7
1998
1999
2000
2001
v
erse event
e
ncy is ske
w
e
less than
0
his require
a
cule, inso
m
v
erse event
e
ncy is ske
w
e
less than
0
s
pect to th
e
y
mptoms t
h
n
jection sit
e
0
0 2002 2004
2001
2002
2003
2004
2005
s associate
d
w
ed toward
s
0
.01, plott
e
ment were
m
nia, inje
c
s associate
d
w
ed toward
s
0
.01, plott
e
e
total nu
m
h
at met this
e
macule, i
n
2006 2008 2
0
2006
2007
2008
2009
d
with alu
m
s
events ass
o
e
d as a fun
c
: fatigue,
s
c
tion site r
e
d
with alu
m
s
events ass
o
e
d as a fun
c
m
ber of alu
m
requireme
n
n
somnia, i
n
0
10
2010
22
4
m
inu
m
-
o
ciated
c
tion of
s
eizure,
e
action,
m
inu
m
-
o
ciated
c
tion of
m
inu
m
-
n
t were:
n
jection
4
0

Entropy 2012, 14 2241
4.3. MMR Vaccine and Autism
The occurrence of the feature “autism” in the vaccines with aluminum were somewhat, but not
dramatically, higher than those without aluminum (556 with, 443 without; p = 0.06); i.e., children with
the autism diagnosis react to both aluminum-containing and non-aluminum-containing vaccines. We
suspect this has to do with the impaired immune function in children with autism, which causes them
to overreact to the MMR vaccine. Given that an adverse reaction to MMR is highly over-represented in
the autism subset, we decided to compare a subset of the database where only the MMR vaccine had
been administered with a comparably-aged subset where the MMR vaccine had not been administered.
The results are shown in Table 4. As might be expected, a diagnosis of infection with measles,
mumps, or chicken pox were highly significantly associated with the MMR vaccine, as well as the
simple word “rash” (p = 0.00000003). However, respiratory tract infection (p = 0.042) and cough
(p = 0.014) were also over-represented in the MMR subset; suggesting that children with an infection
are more likely to react adversely to the vaccine. Since children with the autism diagnosis have a
compromised immune function, they are more likely to be sick at the time of the injection. But, most
interesting for our purposes were the association of fever (p = 0.024) and autism (p = 0.0067) with
MMR. There were a total of 1840 adverse reactions mentioning fever in the MMR set. This suggests to
us that the acetaminophen connection may be correct―that the fever associated with MMR exposure
is treated with acetaminophen, which then becomes toxic to the brain of the child predisposed toward
autism, because of their inability to dispose of it. Acetaminophen would also deplete sulfate needed to
detoxify aluminum in any concurrent aluminum-containing vaccine such as DTaP.
Table 4. Symptoms associated with MMR vaccine administered to children under six years
old, with a p-value less than 0.05.
Symptom C1 MMR C2 not MMR p-value
Rash 2197 745 3.0E-8
Chicken pox 311 23 6.6E-5
Mumps 217 0 0.00012
Face Oedema 232 28 0.00036
Measles 59 4 0.0089
Autism 168 58 0.0067
Cough 191 90 0.014
Fever 1840 1584 0.024
Hematoma 52 12 0.026
Conjunctivitis 42 7 0.027
Lymph Node Pain 25 0 0.028
Respiratory Infection 50 16 0.042
Blister 327 232 0.043
4.4. Hepatitis B Vaccine and Autism
An historical account of the introduction of mandatory vaccination at birth against Hep-B is
presented in [114]. In 1991, the Advisory Committee on Immunization Practices (ACIP) of the Centers
for Disease Control (CDC) recommended that all infants be injected with the first dose of hepatitis B

Entropy 2012, 14 2242
vaccine at birth. Since the states control mandatory vaccination policy, this recommendation was
gradually put into law in nearly all of the states over the subsequent decade. By 1998, most children in
America were required to show proof of three doses of Hep-B prior to entering public school. Since
Hep-B contains both mercury and aluminum, and since it is administered at birth, it is likely to be a
major factor contributing to the steady rise in autism-related events in the latter half of the 1990's.
The practice of requiring Hep-B administration at birth is likely to be extremely dangerous to
children who are born with a sulfur deficiency. Furthermore, Hep-B booster shots are often
administered in conjunction with the varicella vaccine (chicken pox). Children with a compromised
immune system can respond to the live varicella vaccine by coming down with full blown chicken pox,
and the infection in turn leads to increased vulnerability to the aluminum contained in the Hep-B vaccine.
Table 5. Symptoms associated with Hep-B vaccine administered to children under six
years old, with a p-value less than 0.05. The values obtained for aluminum over all age
groups are shown on the right for comparison purposes. The two symptoms at the top were
not statistically significantly associated with aluminum, and are likely attributable to the
compounding effect of the simultaneously administered varicella vaccine.
Symptom C1
Hep-B
C2 not
Hep-B
p-value C1
w/ Al3+
C2
w/o Al3+
p-value
Rash 818 299 4.2E-5 11649 11109 -
chicken pox 80 3 0.0038 523 1152 -
Autism 108 1 0.0014 556 443 0.06
Macule 163 75 0.016 4702 3098 0.000016
Cellulitis 56 6 0.012 2087 1089 0.000024
Blister 188 53 0.0030 4275 3066 0.00015
Seizure 179 115 0.051 3331 2350 0.00028
Infection 78 12 0.0085 1358 927 0.0026
Abscess 74 26 0.029 1205 918 0.012
Death 38 6 0.030 483 303 0.011
Low appetite 32 2 0.025 368 252 0.031
Motivated by these arguments, we decided to compare vaccinations that include Hep-B with those
that do not, over the age range from zero to six. Table 4 shows results for all symptoms with a p-value
less than 0.05. The counts and p-values we obtained for aluminum are shown alongside the results for
Hep-B for easy comparison.
These results are a little hard to interpret because there is a mixture of responses to Hep-B,
responses to the associated varicella, and compounded responses. However, we can plausibly assume
that “rash” and “chicken pox” are primarily due to varicella. “Infection” shows up significantly in both
the Hep-B and the aluminum columns. This reflects the fact that an associated infection (whether a
simple cold or the chicken pox or something else) increases the risk to aluminum toxicity, due to the
additional burden on the immune system.
All of the significant symptoms in the table—macule, cellulitis, blister, seizure, abscess, death, and
low appetite—are also significant symptoms associated with the vaccines containing aluminum. This

Entropy 2012, 14 2243
result further supports the possibility that the aluminum in these vaccines administered to young
children may be even more toxic than the mercury.
A highly significant correlation is found between “autism” and “Hep-B” (p = 0.0014), confirming
the results reported in [89]. The association of aluminum-containing vaccines in general with autism
does not quite make statistical significance (p = 0.06) compared to non-aluminum-containing vaccines.
We explain this observation through the high fever associated with MMR, a non-aluminum-containing
vaccine, that leads to the common practice of administering acetaminophen [25], which the autistic
child cannot adequately detoxify. However, the fact that autism is so clearly associated with Hep-B
gives one pause.
4.5. Limitations of the VAERS Database and the Experiments
Cases of vaccine injury are most likely vastly underreported by physicians to VAERS, as has been
observed for physician reports of drug adverse reactions [115]. We identified only 1,734 mentions of
autism in the entire dataset, whereas the National Vaccine Injury Compensation Program, established
in 1988, reports over 5,000 claims that autism is associated with vaccines. Another limitation is that it
is not easy to distinguish cases where autism may have been a preexisting condition affecting the
child's sensitivity to the vaccine, as contrasted with cases where the vaccine may have preceded, and
therefore may potentially be causative in, a later diagnosis of autism. Finally, both patients and
physicians can submit reports, so quality control due to reporting bias or lack of expertise may be an
issue. Not all of the reports contain a record of the date of the vaccination, and this introduces some
error in the temporal relationships.
5. Discussion
Autism is a disorder affecting cognitive and social skills that has severe implications on the ability
of the affected individual to lead a productive and independent life. The alarming increase in the
incidence of ASD in the last decade suggests that, while genetic factors are contributory,
environmental triggers must also play a decisive role. In this paper, we argue that ASD is a condition
characterized by a serum deficiency in sulfur metabolites, particularly the sulfate anion, which results
in an inability to safely dispose of mercury, aluminum, and acetaminophen.
While the autism community has focused on the mercury in thimerosal as the main culprit in
vaccines, our studies with the VAERS database have identified aluminum and acetaminophen as being
likely even more damaging than mercury. Aluminum binds strongly to sulfur-containing molecules,
and the body depends on sulfur for the proper elimination of both aluminum and acetaminophen, as
well as mercury. Because of the sulfur deficiencies, aluminum, mercury and acetaminophen likely
accumulate in the autistic brain, leading to further damage.
In [116], it is argued that safety assessments for vaccines have not included appropriate toxicity
studies because vaccines have not been viewed as inherently toxic, but that this point of view should
be revisited in light of the increased awareness of the potential toxicity of aluminum, particularly for
infants and young children. They argue further that it is now well established that a bidirectional
neuro-immune cross-talk regulates both the immune system and brain function.

Entropy 2012, 14 2244
The incidence of autism-related adverse events in the VAERS database continued to rise over the
time period after the amount of thimerosal in the vaccines had been sharply reduced. We hypothesize
that this unanticipated consequence is due to simultaneous increases in the aluminum content,
attributed to an increased number of required vaccines, intentional addition of aluminum to achieve an
adjuvant effect, as well as the likely further accumulation of aluminum as a consequence of leaching,
given the new practice of storage in individual glass vials with rubber stoppers. We identified several
severe adverse reactions that were much more prevalent in reports from the second decade of the data,
and showed that these same symptoms were also much more prevalent for reports involving
aluminum-containing vaccines compared to reports on vaccines without aluminum, over the entire data
set. These symptoms include seizure, cyanosis, gaze palsy, depression, fatigue, insomnia, and death.
Possibly contradictory to our proposal is a study which showed elevations of lead, mercury and
uranium in hair analyses of 40 children with autism compared with 40 controls, but these authors
found no elevation of aluminum in the hair [117]. However, the result on mercury contradicts another
study which showed reduced mercury in the hair of infants with autism [118], and a third study which
showed no statistical difference in mercury content of hair between children with autism and
controls [119]. A study in rats showed that oral antibiotics dramatically inhibit mercury excretion to
10% of normal levels [120]. It is conceivable that an inability to export aluminum into the hair, due to
severe sulfate depletion, could complicate the interpretation of a metric based on aluminum content in hair.
The depleted supply of sulfate in the blood stream leads to increased vulnerability to vascular stress,
in turn leading to excess immune cell activation, inflammation, permeability leaks, and blood clots,
attributable mainly to a low ZP. This same deficiency interferes with the child’s ability to dispose of
the aluminum, which eventually accumulates in the brain and interferes with neural transmission. It is
also likely that further aluminum exposure comes from aluminum in skin products such as high SPF
sunscreen, particularly for the child whose barrier function is defective due to inadequate cholesterol
sulfate and filaggrin in the epidermis. Other potential sources of aluminum are aluminum flocking
agents in municipal water supplies, aluminum leaching from aluminum baby formula cans, and
aluminum in the human milk supply to the breastfeeding infant, absorbed by the mother from
sunscreen, antiperspirants, antacid medications, cooking utensils, etc.
Our specific studies on the MMR vaccine and the Hep-B vaccine further support our theories
involving aluminum and acetaminophen toxicity. In an analysis of the distribution of vaccine types in
events associated with autism versus the controls, we determined that MMR was highly over-
represented in the cases associated with autism. A possible explanation is that the high fever associated
with a reaction to MMR led to the administration of acetaminophen, whose safe disposal, like that of
aluminum, depends on an adequate serum supply of bio-sulfates. The frequent presence of concurrent
aluminum-containing vaccines would contribute synergistically to toxicity.
We hypothesize that the fever associated with MMR results in the administration of acetaminophen,
which, in conjunction with the intense immune response to live viruses, becomes toxic to the
vulnerable child. Most of the symptoms associated with Hep-B administration to children under 6
years old are also associated with aluminum-containing vaccines in general and over all age groups,
further bolstering the hypothesis that the aluminum in the vaccine is a major source of toxicity. A
strong association between Hep-B and autism also suggests that aluminum may contribute to autism.

Entropy 2012, 14 2245
This strong association does not however exclude mercury as a contributor to autism, given that Hep B has
both mercury and aluminum. In fact, mercury and aluminum together may be synergistically toxic [113].
If our hypothesis is correct, then it should be relatively easy and very cost-effective to implement a
solution to the problem. Both women of childbearing age and children should be encouraged to
consume foods that are rich in sulfur and to spend considerable time outdoors without sunscreen on
sunny days. It might be prudent to implement a screening test for sulfate and/or glutathione
concentration in the blood prior to administration of an aluminum-containing vaccine, and to waive the
vaccine or consider a non-aluminum-containing alternative if sulfate or glutathione levels are
insufficient. A delay by one month of the current practice of Hep-B administration at birth seems
warranted. The practice of including aluminum in the so-called “placebo” in vaccine trials should be
abolished, so that the effects of aluminum adjuvant can be formally measured in a premarket phase. It
would also be highly recommended to reconsider whether the increased immune response associated
with aluminum adjuvant is worth the price in terms of increased risk of adverse reactions. Based upon
our statistical research of the VAERS database, we would encourage the vaccine industry to consider
omitting aluminum adjuvant doping of all vaccines for both children and adults.
In future work, we plan to create and maintain a web site where users can intelligently search the
VAERS database, asking questions in spoken or typed natural language, such as, “Is there an
association between miscarriage and the Gardasil vaccine?” An intuitive graphical interface will also
help users easily find adverse event reports relevant to their personal experiences. This system will be
modeled after a similar system we have already constructed for prescription drugs [121]. We believe
that the VAERS database is a rich resource, many of whose secrets are yet to be revealed.
6. Conclusion
In this paper, we have presented some analyses of the VAERS database which strongly suggest that
the aluminum in vaccines is toxic to vulnerable children. While we have not shown that aluminum is
directly causative in autism, the compelling evidence available from the literature on the toxicity of
aluminum, combined with the evidence we present for severe adverse reactions occurring much more
frequently following administration of aluminum-containing vaccines as compared to non-aluminum-
containing vaccines, suggests that neuronal damage due to aluminum penetration into the nervous
system may be a significant factor in autism. The fact that mentions of autism rose steadily
concomitant with significant increases in the aluminum burden in vaccines, is highly suggestive.
However, it is possible that other factors, such as more aggressive reporting or simultaneous increases
in other environmental toxins, e.g., herbicides or pesticides, or aluminum in other products such as
antiperspirants and antacids, may have contributed to these observed increases. We also observed a
strong correlation between the MMR vaccine and autism, which we suggest could be explained by the
effects of acetaminophen.
We have proposed elsewhere that an impairment in cholesterol sulfate synthesis in the skin and in
the vasculature may be causative in autism, and we argue here that vaccines can act synergistically
with this impairment in the vulnerable child. We propose that simple corrective measures such as
increased sunlight exposure and decreased use of sunscreen may help protect a child from a severe

Entropy 2012, 14 2246
reaction to aluminum-containing vaccines, but we also feel that the vaccine industry should find a way
to reduce or even eliminate the aluminum content in vaccines.
Acknowledgements
This work was funded in part by Quanta Computer under the Qmulus Initiative. The authors are
grateful to three anonymous reviewers who provided outstanding comments that led to a greatly
improved quality of the document.
References
1. Dawson, G.; Toth, K.; Abbott, R.; Osterling, J.; Munson, J.; Estes, A.; Liaw, J. Early social
attention impairments in autism: social orienting, joint attention, and attention to distress. Dev.
Psychol. 2004, 40, 271–283.
2. Ashwood, P.; Wills, S.; van de Water, J. The immune response in autism: a new frontier for
autism research. J. Leukoc. Biol. 2006, 80, 1–15.
3. Castellani, M.L.; Conti, C.M.; Kempuraj, D.J.; Salini, V.; Vecchiet, J.; Tete, S.; Ciampoli, C.;
Conti, F.; Cerulli, G.; Caraffa, A.; et al. Autism and immunity: Revisited study. Int. J.
Immunopathol. Pharmacol. 2009, 22, 15–19.
4. Ratajczak, H.V. Theoretical aspects of autism: Causes—a review. J. Immunotoxicol. 2011, 8, 68–79.
5. Oller, J.W., Jr. The antithesis of entropy: Biosemiotic communication from genetics to human
language with special emphasis on the immune systems. Entropy 2010, 12, 631–705.
6. Newschaffer, C.J.; Croen, L.A.; Daniels, J.; Giarelli, E.; Grether, J.K.; Levy, S.E.; Mandell, D.S.;
Miller, L.A.; Pinto-Martin, J.; Reaven, J.; et al. The epidemiology of autism spectrum disorders.
Annu. Rev. Publ. Health 2007, 28, 235–258.
7. Baio, J. Prevalence of Autism Spectrum Disorders Autism and Developmental Disabilities
Monitoring Network, 14 Sites, United States, 2008; Morbidity and Mortality Weekly Report;
Centers for Disease Control and Prevention: Atlanta, GA, 2012.
8. Oller, J.W., Jr.; Oller, S.D. Autism: The Diagnosis, Treatment, and Etiology of the Undeniable
Epidemic; Jones and Bartlett Publishers: Sudbury, MA, USA, 2010.
9. Stankovic, M.; Lakic, A.; Ilic, N. Autism and autistic spectrum disorders in the context of new
DSM-V classification, and clinical and epidemiological data. Srp. Arh. Celok. Lek. 2012, 140,
236–243.
10. Herbert, M.R.; Russo, J.P.; Yang, S.; Roohi, J.; Blaxill, M.; Kahler, S.G.; Cremer, L.; Hatchwell, E.
Autism and environmental genomics. Neurotoxicology 2006, 27, 671–684.
11. Law, P.; Law, J.K.; Rosenberg, R.E.; Anderson, C.; Samango-Sprouse, C. Immunization beliefs
and practices among autism families. Presented at International Meeting for Autism Research,
Philadelphia, PA, USA, 21 May 2010.
12. Meldgaard, M.K.; Hviid, A.; Vestergaard, M.; Schendel, D.; Wohlfahrt, J.; Thorsen, P.; Olsen, J.;
Melbye, M. A population-based study of measles, mumps, and rubella vaccination and autism.
N. Engl. J. Med. 2002, 347, 1477–1482.
13. Campion, E.W. Suspicions about the safety of vaccines. N. Engl. J. Med. 2002, 347, 1474–1475.

Entropy 2012, 14 2247
14. DeLong, G. A positive association found between autism prevalence and childhood vaccination
uptake across the U.S. population. J. Toxicol. Env. Health A 2011, 74, 903–916.
15. Seneff, S.; Davidson, R.; Mascitelli, L. Might cholesterol sulfate deficiency contribute to the
development of autistic spectrum disorder? Med. Hypotheses 2012, 8, 213–217.
16. Higashi, Y.; Fuda, H.; Yanai, H.; Lee, Y.; Fukushige, T.; Kanzaki, T.; Strott, C.A. Expression of
cholesterol sulfotransferase (SULT2B1b) in human skin and primary cultures of human
epidermal keratinocytes. J. Invest. Dermatol. 2004, 122, 1207–1213.
17. Frustaci, A.; Neri, M.; Cesario, A.; Adams, J.B.; Domenici, E.; Dalla-Bernardina, B.; Bonassi, S.
Oxidative stress-related biomarkers in autism: Systematic review and meta-analyses. Free Radic.
Biol. Med. 2012, 52, 2128–2141.
18. Stipanuk, M.H.; Coloso, R.M.; Garcia, R.A.; Banks, M.F. Cysteine concentration regulates
cysteine metabolism to glutathione, sulfate and taurine in rat hepatocytes. J. Nutr. 1992, 122,
420–427.
19. Geier, D.A.; Kern, J.K.; Garver, C.R.; Adams, J.B.; Audhya, T.A.; Nata, R.; Geier, M.R.
Biomarkers of environmental toxicity and susceptibility in autism. J. Neurol. Sci. 2009, 280,
101–108.
20. Geier, D.A.; Kern, J.K.; Garver, C.R.; Adams, J.B.; Audhya, T.A.; Geier, M.R. A prospective
study of transsulfuration biomarkers in autistic disorders. Neurochem. Res. 2009, 34, 386–393.
21. Horan, F.E.; Hirsch, F.G.; Wood, L.A.; Wright, I.S. Surface effects on blood-clotting
components as determined by zeta-potentials. J. Clin. Invest. 1950, 29, 202–211.
22. Davidson, R.M.; Seneff, S. The Initial Common Pathway of Inflammation, Disease, and Sudden
Death. Entropy 2012, 14, 1399–1442.
23. Dai, G.; Chou, N.; He, L.; Gyamfi, M.A.; Mendy, A.J.; Slitt, A.L.; Klaassen, C.D.; Wan, Y.-J.Y.
Retinoid X receptor alpha regulates the expression of glutathione S-transferase genes and
modulates acetaminophen-glutathione conjugation in mouse liver. Mol. Pharmacol. 2005, 68,
1590–1596.
24. Coughtrie, M.W.; Bamforth, K.J.; Sharp, S.; Jones, A.L.; Borthwick, E.B.; Barker, E.V.;
Roberts, R.C.; Hume, R.; Burchell, A. Sulfation of endogenous compounds and Xenobiotics:
Interactions and function in health and disease. Chem. Biol. Interact. 1994, 92, 247–256.
25. Schnell, R.C.; Park, K.S.; Davies, M.H.; Merrick, B.A.; Weir, S.W. Protective effects of
selenium on acetaminophen-induced hepatotoxicity in the rat. Toxicol. Appl. Pharmacol. 1988,
95, 1–11.
26. Damodaran, M.; Priya, L.; Geetha, A. Level of trace elements (copper, zinc, magnesium and
selenium) and toxic elements (lead and mercury) in the hair and nail of children with autism.
Biol. Trace Elem. Res. 2011, 142, 148–158.
27. Becker, K.G.; Schultz, S.T. Similarities in features of autism and asthma and a possible link to
acetaminophen use. Med. Hypotheses 2010, 74, 7–11.
28. Becker, K.G. Autism, asthma, inflammation, and the hygiene hypothesis. Med. Hypotheses 2007,
69, 731–740.
29. Magalhäes, E.S.; Pinto-Mariz, F.; Bastos-Pinto, S.; Pontes A.T.; Prado, E.A.; de Azevedo, L.C.
Immune allergic response in Asperger syndrome. J. Neuroimmunol. 2009, 216, 108–112.

Entropy 2012, 14 2248
30. Nakae, H.; Hanyu, O.; Fuda, H.; Strott, C.A. Novel role of cholesterol sulfate in gene regulation
during skin development. FASEB J. 2008, 22, 782.
31. Presland, R.B. Function of filaggrin and caspase-14 in formation and maintenance of the
epithelial barrier. Dermatol. Sinica 2009, 27, 1–14.
32. Palmer, C.N.; Ismail, T.; Lee, S.P.; Terron-Kwiatkowski, A.; Zhao, Y.; Liao, H.; Smith, F.J.;
McLean, W.H.; Mukhopadhyay, S. Filaggrin null mutations are associated with increased asthma
severity in children and young adults. J. Allergy Clin. Immunol. 2007, 120, 64–68.
33. Palmer, C.N.; Irvine, A.D.; Terron-Kwiatkowski, A.; Zhao, Y.; Liao, H.; Lee, S.P.; Goudie,
D.R.; Sandilands, A.; Campbell, L.E.; Smith, F.J.; et al. Common loss-of-function variants of the
epidermal barrier protein filaggrin are a major predisposing factor for atopic dermatitis. Nat.
Genet. 2006, 38, 441–446.
34. Schuttelaar, M.L.A.; Kerkhof, M.; Jonkman, M.F.; Koppelman, G.H.; Brunekreef, B.;
de Jongste, J.C.; Wijga, A.; McLean, W.H.I.; Postma, D.S. Filaggrin mutations in the onset of
eczema, sensitization, asthma, hay fever and the interaction with cat exposure. Allergy 2009, 64,
1758–1765.
35. Gonzalez, M.A.; Roma, M.G.; Bernal, C.A.; de Lujan Alvarez, M.; Carrillo, M.C. Biliary
secretory function in rats chronically intoxicated with aluminum. Toxicol. Sci. 2004, 79, 189–
195.
36. Griffiths, W.J.; Sjövall, J. Bile acids: analysis in biological fluids and tissues. J. Lipid Res. 2010,
51, 23–41.
37. Yeh, Y.-H.; Lee, Y.-T.; Hsieh, H.-S.; Hwang, D.-F. Effect of taurine on toxicity of aluminum in
rats. E Spen Eur. E J. Clin. Nutr. Metab. 2009, 4, e187–e192.
38. Siri, K.; Lyons, T. Cutting-Edge Therapies for Autism 2011–2012; Skyhorse Publishing: New
York, NY, USA, 2011; p. 74.
39. Adams, J.B.; Bara, M.; Geis, E.; Mitchell, J.; Ingram, J.; Hensley, A.; Zappia, I.; Newmark, S.;
Gehn, E.; Rubin, R.A.; et al. Safety and efficacy of oral DMSA therapy for children with autism
spectrum disorders: Part A-Medical results. BMC Pharmacol. Toxicol. 2009, 9, 16.
40. Adams, J.B.; Bara, M.; Geis, E.; Mitchell, J.; Ingram, J.; Hensley, A.; Zappia, I.; Newmark, S.;
Gehn, E.; Rubin, R.A.; et al. Safety and efficacy of oral DMSA therapy for children with autism
spectrum disorders: Part B-Behavioral results. BMC Clin. Pharmacol. 2009, 9, 17.
41. Cannell, J.J. Autism and vitamin D. Med. Hypotheses. 2008, 70, 750–759.
42. Troncoso, J.C.; March, J.L.; Häner, M.; Aebi, U. Effect of aluminum and other multivalent
cations on neurofilaments in vitro: An electron microscopic study. J. Struct. Biol. Mar. 1990,
103, 2–12.
43. Joshi, J.G. Neurochemical hypothesis: participation by aluminum in producing critical mass of
colocalized errors in brain leads to neurological disease. Comp. Biochem. Physiol. C 1991, 100,
103–105.
44. Theoharides, T.C.; Zhang, B. Hypothesis: Neuro-inflammation, blood-brain barrier, seizures and
autism. J. Neuroinflamm. 2011, 8, 168.
45. Tomljenovic, L.; Shaw, C.A. Aluminum vaccine adjuvants: Are they safe? Curr. Med. Chem.
2011, 18, 2630–2637.

Entropy 2012, 14 2249
46. Villa. L.L.; Costa, R.L.; Petta, C.A.; Andrade, R.P.; Ault, K.A.; Giuliano, A.R.; Wheeler, C.M.;
Koutsky, L.A.; Malm, C.; Lehtinen, M.; et al. Prophylactic quadrivalent human papillomavirus
(types 6, 11, 16, and 18) L1 virus-like particle vaccine in young women: A randomised double-
blind placebo-controlled multicentre phase II efficacy trial. Lancet Oncol. 2005, 6, 271–278.
47. Harper, D.M.; Franco, E.L.; Wheeler, C.; Ferris, D.G.; Jenkins, D.; Schuind, A.; Zahaf, T.; Innis,
B.; Naud, P.; de Carvalho, N.S.; et al. Efficacy of a bivalent L1 virus-like particle vaccine in
prevention of infection with human papillomavirus types 16 and 18 in young women: A
randomised controlled trial. Lancet 2004, 364, 1757–1765.
48. Verstraeten, T.; Descamps, D.; David, M.P.; Zahaf, T.; Hardt, K.; Izurieta, P.; Dubin, G.; Breuer,
T. Analysis of adverse events of potential autoimmune aetiology in a large integrated safety
database of AS04 adjuvanted vaccines. Vaccine 2008, 26, 6630–6638.
49. Garland, S.M.; Hernandez-Avila, M.; Wheeler, C.M. Perez, G.; Harper, D.M.; Leodolter, S.;
Tang, G.W.K.; Ferris, D.G.; Steben, M.; Bryan, J.; et al. Quadrivalent vaccine against human
papillomavirus to prevent anogenital diseases. N. Engl. J. Med. 2007, 356, 1928–1943.
50. Redhead, K.; Quinlan, G.J.; Das, R.G.; Gutteridge, J.M. Aluminium-adjuvanted vaccines transiently
increase aluminium levels in murine brain tissue. Pharmacol. Toxicol. 1992, 70, 278–280.
51. Poole, R.L.; Hintz, S.R.; Mackenzie, N.I.; Kerner, J.A., Jr. Aluminum exposure from pediatric
parenteral nutrition: meeting the new FDA regulation. J. Parenter. Enteral. Nutr. 2008 32, 242–246.
52. Tomljenovic, L. Aluminum and Alzheimer's disease: after a century of controversy, is there a
plausible link? J. Alzheimers Dis. 2011, 23, 567–598.
53. MacLeod, M.K.L.; McKee, A.S.; David, A.; Wang, J.; Mason, R.; Kapplera, J.W.; Marrack, P.
Vaccine adjuvants aluminum and monophosphoryl lipid A provide distinct signals to generate
protective cytotoxic memory CD8 T cells. Proc. Natl. Acad. Sci. USA 2011, 108, 7914–7919.
54. Shoenfeld, Y.; Agmon-Levin, N. ‘ASIA’-autoimmune/inflammatory syndrome induced by
adjuvants. J. Autoimmun. 2011, 36, 4–8.
55. Exley, C.; Siesjö, P.; Eriksson, H. The immunobiology of aluminium adjuvants: How do they
really work? Trends Immunol. 2010, 31, 103–109.
56. Wittayanukulluk, A.; Jiang, D.; Regnier, F.E.; Hem, S.L. Effect of microenvironment pH of
aluminum hydroxide adjuvant on the chemical stability of adsorbed antigen. Vaccine 2004, 22,
1172–1176.
57. Blaxill, M.F.; Redwood, L.; Bernard, S. Thimerosal and autism? A plausible hypothesis that
should not be dismissed. Med. Hypotheses 2004, 62, 788–794.
58. Centers for Disease Control and Prevention. Thimerosal in vaccines: A joint statement of the
American Academy of Pediatrics and the Public Health Service. MMWR Morb. Mortal Wkly.
Rep. 1999, 48, 563–565.
59. Bohrer, D.; do Nascimento, P.C.; Binotto, R.; Becker, E. Influence of the glass packing on the
contamination of pharmaceutical products by aluminium. Part III: Interaction container-
chemicals during the heating for sterilisation. J. Trace Elem. Med. Biol. 2003, 17, 107–115.
60. Cuthbertson, B.; McBay, W.E.; Welch, A.G.; Perry, R.J.; Foster, P.R. Aluminium and human
albumin solutions. Brit. Med. J. 1987, 295, 1062.
61. Zatta, P.; Alfrey, A.C. Aluminium Toxicity in Infants' Health and Disease; World Scientific
Publishers: Singapore, 1997; p. 192.

Entropy 2012, 14 2250
62. Wills, M.R.; Savory, J. Water content of aluminum, dialysis dementia, and osteomalacia.
Environ. Health Persp. 1985, 63, 141–147.
63. Pogue, A.I.; Li, Y.Y.; Cui, J.-G.; Zhao, Y.; Kruck, T.P.A.; Percy, M.E.; Tarr, M.A.; Lukiw, W.J.
Characterization of an NF-jB-regulated, miRNA-146a-mediated down-regulation of complement
factor H (CFH) in metal-sulfate-stressed human brain cells. J. Inorg. Biochem. 2009, 103,
1591–1595.
64. Pogue, A.I.; Jones, B.M.; Bhattacharjee, S.; Percy, M.E.; Zhao, Y.; Lukiw, W.J. Metal-sulfate
induced generation of ROS in human brain cells: Detection using an isomeric mixture of 5- and
6-carboxy-2′,7′-dichlorofluoresce in diacetate (carboxy-DCFDA) as a cell permeant tracer. Int. J.
Mol. Sci. 2012, 13, 9615–9626.
65. Del Giudice, E.; Spinetti, P.R.; Tedeschi, A. Water dynamics at the root of metamorphosis in
living organisms. Water 2010, 2, 566–586.
66. Binhi, V.N.; Rubin, A.B. Magnetobiology: the kT paradox and possible solutions. Electromagn.
Biol. Med. 2007, 26, 45–62.
67. Verstraeten, S.V.; Aimo, L.; Oteiza, P.I. Aluminium and lead: molecular mechanisms of brain
toxicity. Arch. Toxicol. 2008, 82, 789–802.
68. Aimanianda, V.; Haensler, J.; Lacroix-Desmazes, S.; Kaveri, S.V.; Bayry, J. Novel cellular and
molecular mechanisms of induction of immune responses by aluminum adjuvants. Trends
Pharmacol. Sci. 2009, 30, 287–295.
69. Cheung, W.Y. Calmodulin plays a pivotal role in cellular regulation. Science 1980, 207, 19–27.
70. Büsselberg, D.; Platt, B.; Haas, H.L.; Carpenter, D.O. Voltage gated calcium channel currents
of rat dorsal root ganglion (DRG) cells are blocked by A13+. Brain Res. 1993, 622, 163–168.
71. Siegel, N.; Haug, A. Aluminum interaction with calmodulin. Evidence for altered structure and
function from optical and enzymatic studies. Biochim. Biophys. Acta 1983, 744, 36–45.
72. Lemire, J.; Appanna, V.D. Aluminum toxicity and astrocyte dysfunction: A metabolic link to
neurological disorders. J. Inorg. Biochem. 2011, 105, 1513–1517.
73. Lemire, J.; Mailloux, R.; Puiseux-Dao, S.; Appanna, V.D. Aluminum-induced defective
mitochondrial metabolism perturbs cytoskeletal dynamics in human astrocytoma cells.
J. Neurosci. Res. 2009, 87, 1474–1483.
74. Cauwels, A.; Janssen, B.; Buys, E.; Sips, P.; Brouckaert, P. Anaphylactic shock depends on PI3K
and eNOS-derived NO. J. Clin. Invest. 2006, 116, 2244–2251.
75. Hazlett, H.C.; Poe, M.; Gerig, G.; Smith, R.G.; Provenzale, J.; Ross, A.; Gilmore, J.; Piven, J.
Magnetic resonance imaging and head circumference study of brain size in autism: Birth through
age 2 years. Arch. Gen. Psychiatry 2005, 62, 1366–1376.
76. Courchesne, E. Brain development in autism: Early overgrowth followed by premature arrest of
growth. Ment. Retard. Dev. Disabil. Res. Rev. 2004, 10, 106–111.
77. Llansola, M.; Miñana, M.-D.; Montoliu, C.; Saez, R.; Corbalán, R.; Manzo, L.; Felipo, V.
Prenatal exposure to aluminum reduces expression of neuronal nitric oxide synthase and of
soluble guanylate cyclase and impairs glutamatergic neurotransmission in rat cerebellum. J.
Neurochem. 1999, 73, 712–718.
78. Carter, D.C.; Ho, J.X. Structure of Serum Albumin. Adv. Protein Chem. 1994, 45, 153–203.
79. Zalups, R.K. Molecular interactions with mercury in the kidney. Pharmacol. Rev. 2000, 52, 113–143.

Entropy 2012, 14 2251
80. Rezwan, K.; Meier, L.P.; Rezwan, M.; Vörös, J.; Textor, M.; Gauckler, L.J. Bovine serum
albumin adsorption onto colloidal Al2O3 particles: A new model based on Zeta potential and
UV-Vis measurements. Langmuir 2004, 20, 10055–10061.
81. Clarkson, T.W.; Nordberg, G.F.; Sager, P.R. Reproductive and developmental toxicity of metals.
Scand. J. Work Environ. Health 1985, 11, 145–154.
82. Burbacher, T.M.; Shen, D.D.; Liberato, N.; Grant, K.S.; Cernichiari, E.; Clarkson, T.
Comparison of blood and brain mercury levels in infant monkeys exposed to methylmercury or
vaccines containing thimerosal. Environ. Health Perspect. 2005, 113, 1015–1021.
83. Hornig, M.; Chian, D.; Lipkin, W.I. Neurotoxic effects of postnatal thimerosal are mouse strain
dependent. Mol. Psychiatr. 2004, 9, 1–13.
84. Templeton, D.M.; Chaitua, N. Effects of divalent metals on the isolated rat glomerulus.
Toxicology 1990, 61, 119–133.
85. Wakefield, A.J. MMR vaccination and autism. Lancet 1999, 354, 949–950;
86. Madsen, K.M.; Lauritsen, M.B.; Pedersen, C.B.; Thorsen, P.;Plesner, A.M.; Andersen, P.H.;
Mortensen, P.B. Thimerosal and the occurrence of autism: Negative ecological evidence from
Danish population-based data. Pediatrics 2003, 112, 604–606.
87. Hunter, R.L. Overview of vaccine adjuvants: present and future. Vaccine 2002, 20, S7–S12.
88. Eickhoff, T.C.; Myers, M. Workshop summary Aluminum in vaccines. Vaccine 2002, 20, S1–S4.
89. Gallagher, O.M.; Goodman, M.S. Hepatitis B vaccination of male neonates and autism diagnosis,
NHIS 1997–2002. J. Toxicol. Environ. Health A 2010, 73, 1665–1677.
90. Zinka, B.; Rauch, E.; Buettner, A.; Ruëff, F.; Penning, R. Unexplained cases of sudden infant
death shortly after hexavalent vaccination. Vaccine 2006, 24, 5779–5780.
91. Von Kries, R.; Toschke, A.M.; Strassburger, K.; Kundi, M.; Kalies, H.; Nennstiel, U.; Jorch, G.;
Rosenbauer, J.; Giani, G. Sudden and unexpected deaths after the administration of hexavalent
vaccines (diphtheria, tetanus, pertussis, poliomyelitis, hepatitis B, Haemophilius influenzae type
b): Is there a signal? Eur. J. Pediatr. 2005, 164, 61–69.
92. Traversa, G.; Spila-Alegiani, S.; Bianchi, C.; degli Atti, M.C.; Frova, L.; Massari, M.; Raschetti, R.;
Salmaso, S.; Scalia Tomba, G. Sudden unexpected deaths and vaccinations during the first two
years of life in Italy: A case series study. PLoS One 2011, 6, e16363.
93. Kuhnert, R.; Hecker, H.; Poethko-Müller, C.; Schlaud, M.; Vennemann, M.; Whitaker, H.J.;
Farrington, C.P. A modified self-controlled case series method to examine association between
multidose vaccinations and death. Stat. Med. 2011, 30, 666–677.
94. Brotherton, J.M.; Gold, M.S.; Kemp, A.S.; McIntyre, P.B.; Burgess, M.A.; Campbell-Lloyd, S.
Anaphylaxis following quadrivalent human papillomavirus vaccination. Can. Med. Assoc. J.
2008, 179, 525–533.
95. Pourcyrous, M.; Korones, S.B.; Kristopher, L.A.; Bada, H.S. Primary immunization of premature
infants with gestational age < 35 weeks: Cardiorespiratory complications and C-reactive protein
responses associated with administration of single and multiple separate vaccines simultaneously.
J. Pediatr. 2007, 151, 167–171.
96. Goldman, G.S.; Miller, N.Z. Relative trends in hospitalizations and mortality among infants by
the number of vaccine doses and age, based on the Vaccine Adverse Event Reporting System
(VAERS), 1990-2010. Hum. Exp. Toxicol. 2012, 31, 1012–1021.

Entropy 2012, 14 2252
97. Geier, M.R.; Geier, D.A. Hepatitis B vaccination safety. Ann. Pharmacother. 2002, 36, 370–374.
98. Exley, C.; Swarbrick, L.; Gherardi, R.K.; Authier, F.-J. A role for the body burden of aluminium
in vaccine-associated macrophagic myofasciitis and chronic fatigue syndrome. Med. Hypotheses
2009, 72, 135–139.
99. Dunning, T. Accurate methods for the statistics of surprise and coincidence. Comp. Ling. 1993,
19, 61–74.
100. Liu, J.; Li, A.; Seneff, S. Automatic drug side effect discovery from online patient-submitted
reviews: Focus on statin drugs. In Proceedings of First International Conference on Advances in
Information Mining and Management (I.M.M.M.), Barcelona, Spain, 23–29 October, 2011.
101. Afzal, N.; Murch, S.; Thirrupathy, K.; Berger, L.; Fagbemi, A.; Heuschkel, R. Constipation with
acquired megarectum in children with autism. Pediatrics 2003, 112, 939–942.
102. Gillott, A.; Furniss, F.; Walter, A. Anxiety in high-functioning children with autism. Autism
2001, 5, 277–286.
103. Caputo, D.V.; Mandell, W. Consequence of low birth weight. Dev. Psychol. 1970, 3, 363–383.
104. Lin, B.; Kubushiro, K.; Akiba, Y.; Cui, Y.; Tsukazaki, K.; Nozawa, S.; Iwamori, M. Alteration of
acidic lipids in human sera during the course of pregnancy: Characteristic increase in the
concentration of cholesterol sulfate. J. Chromatogr. B 1997, 704, 99–104.
105. Harumi, J.; Sun, S.; Le, H. Proinflammatory and regulatory cytokine production associated with
innate and adaptive immune responses in children with autism spectrum disorders and
developmental regression. Neuroimmunology 2001, 120, 170–179.
106. Schultz, S.T.; Klonoff-Cohen, H.S.; Wingard, D.L.; Akshoomoff, N.A.; Macera, C.A.; Ji, M.
Acetaminophen (paracetamol) use, measles-mumps-rubella vaccination, and autistic disorder:
The results of a parent survey. Autism 2008, 12, 293–307.
107. Ghanizadeh, A. Acetaminophen may mediate oxidative stress and neurotoxicity in autism. Med.
Hypotheses 2012, 78, 351–351.
108. Schultz, S.; Desilva, M.; Gu, T.T.; Qiang, M.; Whang, K. Effects of the Analgesic
Acetaminophen (Paracetamol) and its para-Aminophenol Metabolite on Viability of Mouse-
Cultured Cortical Neurons. Basic Clin. Pharmacol. Toxicol. 2011, 110, 141–144.
109. Alberti, A.; Pirrone, P.; Elia, M.; Waring, R.H.; Romano, C. Sulphation deficit in ‘low-
functioning’ autistic children: A pilot study. Biol. Psychiatry 1999, 46, 420–424.
110. Thinktwice Global Vaccine Institute. Available online: www.thinktwice.com, (accessed on 30
July 2012).
111. Centers for Disease Control. Recommended immunization schedules for persons aged 0–18
years―United States, 2010. MMWR Morb. Mortal Wkly. Rep. 2009, 58, 1–4.
112. Centers for Disease Control. Preventing pneumococcal disease among infants and young
children. MMWR Morb. Mortal Wkly. Rep. 2000, 49, 1–38.
113. Haley, B.E. Mercury toxicity: Genetic susceptibility and synergistic effects. Medical Veritas
2005, 2, 535–542.
114. National Vaccine Information Center, Hepatitis B vaccine: The untold story. Avaiable online:
http://www.nvic.org/nvic-archives/newsletter/untoldstory.aspx (accessed on 10 October 2012).

Entropy 2012, 14 2253
115. Scott, H.D.; Thacher-Renshaw, A.; Rosenbaum, S.E.; Waters, W.J., Jr.; Green, M.; Andrews,
L.G.; Faich, G.A. Physician reporting of adverse drug reactions. Results of the Rhode Island
Adverse Drug Reaction Reporting Project. J. Am. Med. Assoc. 1990, 263, 1785–1788.
116. Tomljenovic, L.; Shaw, C.A. Mechanisms of aluminum adjuvant toxicity and autoimmunity in
pediatric populations. Lupus 2012, 21, 223–230.
117. Fido, A.; Al-Saad S. Toxic trace elements in the hair of children with autism. Autism. 2005, 9,
290–298.
118. Holmes, A.S.; Blaxill, M.F.; Haley, B.E. Reduced levels of mercury in first baby haircuts of
autistic children. Int. J. Toxicol. 2003, 22, 277–285.
119. Adams, J.B.; Holloway, C.E.; George, F.; Quig, D. Analyses of toxic metals and essential
minerals in the hair of arizona children with autism and associated conditions, and their mothers.
Biol. Trace Elem. Res. 2006, 110, 193–208.
120. Rowland, I.; Davies, M.; Evans, J. Tissue content of mercury in rats given methylmercury
chloride orally: Influence of intestinal flora. Arch. Environ. Health 1980, 35, 155–160.
121. Liu, J.; Seneff, S. A dialogue system for accessing drug reviews. In Proceedings of Automatic
Speech Recognition and Understanding Workshop (ASRU), Waikoloa, HI, USA, December 2011;
pp. 324–329.
© 2012 by the authors; licensee MDPI, Basel, Switzerland. This article is an open access article
distributed under the terms and conditions of the Creative Commons Attribution license
(http://creativecommons.org/licenses/by/3.0/).